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Cited by 130Alzheimer's disease research and treatmentsProtease and Inhibitor MechanismsCell Adhesion Molecules Research

Tetraspanin12 regulates ADAM10‐dependent cleavage of amyloid precursor protein

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Xu, Daosong, Sharma, Chandan, Hemler, Martin E.·2009·The FASEB Journal
DOI 10.1096/fj.09-133462PMC PMC2775005
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Abstract

Using mass spectrometry, we identified ADAM10 (a membrane‐associated metalloproteinase) as a partner for TSPAN12, a tetraspanin protein. TSPAN12‐ADAM10 interaction was confirmed by reciprocal coimmunoprecipitation in multiple tumor cell lines. TSPAN12, to a greater extent than other tet‐raspanins (CD81, CD151, CD9, and CD82), associated with ADAM10 but not with ADAM17. Overexpression of TSPAN12 enhanced ADAM10‐dependent shedding of amyloid precursor protein (APP) in MCF7 (breast cancer) and SH‐SY5Y (neuroblastoma) cell lines. Conversely, siRNA ablation of endogenous TSPAN12 mark‐edly diminished APP proteolysis in both cell lines. Furthermore, TSPAN12 overexpression enhanced ADAM10 prodomain maturation, whereas TSPAN12 ablation diminished ADAM10 maturation. A palmitoylation‐deficient TSPAN12 mutant failed to associate with ADAM10, inhibited ADAM10‐dependent proteolysis of APP, and inhibited ADAM10 maturation, most likely by interfering with endogenous wild‐type TSPAN12. In conclusion, TSPAN12 serves as a novel and robust partner for ADAM10 and promotes ADAM10 maturation, thereby facilitating ADAM10‐dependent proteolysis of APP. This novel mode of regulating APP cleavage is of relevance to Alzheimer's disease therapy.—Xu, D., Sharma, C., Hemler, M. E. Tetraspanin12 regulates ADAM10‐dependent cleavage of amyloid precursor protein. FASEB J. 23, 3674‐3681 (2009). www.fasebj.org

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  • ADAM10 α-cleavage activity is influenced by growth factors, cytokines and neurotransmitters.

    “Post-translationally, ADAM10 α-cleavage activity is influenced by growth factors, cytokines and neurotransmitters”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [15]

    The Abstract and Discussion report that TSPAN12 promotes ADAM10 maturation and α-secretase activity, supporting post-translational regulation of that activity. They describe growth factors and TNF-α as molecules ADAM10 cleaves, not as regulators of its α-cleavage activity; the copy does not establish regulation by growth factors, cytokines, or neurotransmitters. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Surface trafficking pathways mediated in part by tetraspanin proteins contribute to ADAM10 α-cleavage activity.

    “emerging studies indicate contributions of surface trafficking pathways that are mediated in part by tetraspanin proteins (15–17).”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [15]

    The Discussion (Mechanistic insights) links TSPAN12 localization to ADAM10 function: a mutant partly diverted TSPAN12 from the plasma membrane and impaired ADAM10 maturation and activity. The paper supports a tetraspanin contribution to ADAM10 α-cleavage, but does not establish a surface-trafficking pathway for ADAM10; it reports that TSPAN12 manipulation did not change ADAM10 levels at the cell surface. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Xu, D., Sharma, C., & Hemler, M. E.
Affiliations
Harvard University (US)
Corresponding author
Hemler, Martin E.
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2009-07-08
Volume
23
Issue
11
Pages
3674-3681
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.09-133462
PMC
PMC2775005
OpenAlex
W2118876004
Cited by
130
References
3
Citations by year
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FWCI
7.76
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (GM38903, CA102034)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Keywords
TSPAN12, tetraspanins, ADAM10, amyloid precursor protein, APP proteolysis, palmitoylation, protein-protein interaction, ADAM17, Alzheimer's disease, cancer cell lines
MeSH terms
ADAM10 Protein, Humans, Membrane Proteins, Mutation, Amyloid beta-Protein Precursor, Cell Line, Tumor, ADAM Proteins, Amyloid Precursor Protein Secretases, Gene Knockdown Techniques, Tetraspanins

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